Abstract 2726: A circadian regulator drives tumor lineage plasticity through chromatin bivalency resolution
Bibliographic record
Abstract
Abstract Chromatin bivalency plays an important role in cell lineage specification during development. Cancer therapy resistance involves an extensive reprogramming of gene expression resulting in tumor lineage plasticity (LP). However, the underlying mechanisms are poorly understood. Rev-erb-alpha, a member of the nuclear receptor transcription factor family, plays a key role in regulation of circadian rhythm and metabolism primarily through repression of its target genes. We performed sequential ChIP-seq epigenome profiling of tumor tissues from the clinic and PDX models of prostate cancer and integrated analysis of tumor epigenome and transcriptome. We also treated the PDX models with small-molecule inhibitors of the receptor. We found that most of the tumor LP genes, including those in programs of neurodevelopment, neural signaling, stemness and EMT, are controlled by bivalent promoters with concurrent marking of H3K27me3 and H3K4me3. Our further studies revealed that the bivalent chromatin state resolves during the development of cancer therapy resistance. Interestingly, Rev-erb-alpha plays a critical role in promoting the bivalency resolution and activation of the LP programs. Its pharmacological targeting effectively reverses the bivalency resolution and diminishes the LP in anti-AR therapy-resistant tumors. Therefore, our study establishes that resolution of chromatin bivalency is a major epigenetic mechanism of tumor LP and demonstrates that therapeutic targeting of Rev-erb-alpha represents a novel treatment of advanced prostate cancer. This work was supported by NIH and UC Davis comprehensive cancer center and U.S. Department of Defense. Citation Format: Yatian Yang, Xiong zhang, hongye zou, Eva Corey, Ronald M. Evans, Amina Zoubeidi, Hongwu Chen. A circadian regulator drives tumor lineage plasticity through chromatin bivalency resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2726.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".